This study is designed to investigate genetic factors in age-related eye disease. This will be done in the context of the Beaver Dam Eye Study a large population-based epidemiologic study of age-related eye disease in people 43-86 years of age (n=4,926). The specific diseases of interest are age-related maculopathy and age-related lens opacities, two of the most common causes of decreased vision in older Americans. Using standardized protocols, the presence and severity of these eye conditions were determined based on objective masked gradings of photographs of the retina and lens in the entire population five years ago. Sibships living within the community of Beaver Dam, Wisconsin were ascertained and their records linked for statistical analyses. Segregation analyses were performed using the S.A.G.E. program REG C. A recessively inherited gene could account for about 56% of the variability of the maculopathy score with recessive gene frequency of about 0.35. For nuclear sclerosis, a model of autosomal recessive inheritance accounted for 35% of the sample variability, with an estimated gene frequency of 0.42. For cortical opacity, transmission of a major effect was detected that was not completely one-locus mendelian. There appeared to be an effect of sex. A recessive gene frequency of 0.24 could account for 75% of the variability in males and 45% of the variability in females. The current proposal is to support linkage studies within this population in order to identify genetic loci that are related to these lesions. The Beaver Dam Eye Study population is currently being re-examined using the same protocols as five years ago. Buffy coat is being obtained from each participant. The current grant will entail further data gathering in the field to confirm the initial sibships and to identify other family members (especially cousins) in the community. Given special emphases to location where candidate genes are implicated, "positional cloning" which searches the whole genome for co-segregation with genetic markers that are not necessarily functionally related to the disease, will be used. Markers will be chosen that are approximately equally spaced so that a systematic "global search" is done. The results of this investigation will identify specific genetic patterns for age- related eye diseases and will permit a quantitative estimate of the relative importance of environmental exposures on these conditions. Findings from this study may provide further understanding of the pathogenesis of these diseases and may have public health implications if there are some segments of the population in which preventing environmental exposures may alter disease risk.